13-48411862-T-A

Variant names:

• chr13-48411862-T-A
• rs121434307
• NM_001162498.3:c.562A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_001162498.3(LPAR6):​c.562A>T​(p.Ile188Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: LPAR6 NM_001162498.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.27
• Publications: 9 publications found

Genes affected

LPAR6 (HGNC:15520): (lysophosphatidic acid receptor 6) The protein encoded by this gene belongs to the family of G-protein coupled receptors, that are preferentially activated by adenosine and uridine nucleotides. This gene aligns with an internal intron of the retinoblastoma susceptibility gene in the reverse orientation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2009]

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

RB1 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 13-48411862-T-A is Pathogenic according to our data. Variant chr13-48411862-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPAR6	NM_001162498.3	c.562A>T	p.Ile188Phe	missense_variant	Exon 1 of 1	ENST00000620633.5	NP_001155970.1
RB1	NM_000321.3	c.1695+30419T>A		intron_variant	Intron 17 of 26	ENST00000267163.6	NP_000312.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPAR6	ENST00000620633.5	c.562A>T	p.Ile188Phe	missense_variant	Exon 1 of 1	5	NM_001162498.3	ENSP00000482660.1
RB1	ENST00000267163.6	c.1695+30419T>A		intron_variant	Intron 17 of 26	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000321 AC: 8 AN: 248940 AF XY: 0.0000593

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461576 Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypotrichosis 8 Pathogenic:2

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SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as likely pathogenic for Woolly hair autosomal recessive 1 with or without hypotrichosis. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1); For recessive disorders, detected in trans with a pathogenic variant (PM3); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3). -

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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A known missense variant, c.562A>T in exon 1 of the LPAR6 was identified in the homozygous state in proband (Khan S et al., 2011; Raza et al., 2014). Sanger validation and segregation analysis showed that the variant was present in homozygous state in the proband and in heterozygous state in the parents. The variant is absent in homozygous state in population database gnomAD (v4.1.0) and in-house database of 3429 exomes. This variant was observed in heterozygous state in 33 individuals in gnomAD and absent in in-house database. In-silico prediction tools (CADD, REVEL) are consistent in predicting the variant to be damaging to the LPAR6 protein function. The clinical features observed in the proband are in concordance with woolly hair, autosomal recessive 1, with or without hypotrichosis. Thus, the above-mentioned variant in homozygous state is the cause for the condition observed in proband. -

Wooly hair, autosomal recessive 1, with or without hypotrichosis Pathogenic:1

Aug 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	.;D;.
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	2.0	M;M;M
PhyloP100		6.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Uncertain	0.60
Sift	Benign	0.030	D;.;D
Sift4G	Benign	0.17	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.87		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.82
MPC		0.40
ClinPred		0.67	D
GERP RS		4.6
Varity_R		0.48
gMVP		0.74
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434307; hg19: chr13-48985998;